Project Summary/Abstract Cognitive deficits are the strongest predictor of functional outcome in schizophrenia, and even after the florid psychotic symptoms are treated with antipsychotic drugs, debilitating cognitive deficits persist. Consequently, only 20% of individuals with schizophrenia can work. Cognitive deficits are also seen in early course, minimally treated patients and first-degree relatives. Recent studies point to sleep spindle abnormalities as a target for improving cognitive function in schizophrenia. Patients with schizophrenia have a specific deficit in sleep spindles that is associated with impaired memory consolidation and symptom severity. Sleep spindle deficits are seen in non-psychotic first-degree relatives and antipsychotic nave first episode patients, and constitute an endophenotype that (i) predates the onset of SZ, (ii) persists throughout its course, and (iii) contributes to cognitive deficits and symptoms. Sleep spindles are rapid bursts of 12-15 Hz EEG activity characteristic of Stage 2 non-rapid eye movement sleep that are generated and regulated by the thalamic reticular nucleus (TRN) and related thalamocortical circuitry. Another endophenotype of SZ, sensory gating, is also regulated by TRN circuitry. The TRN, by gating the flow of information from the thalamus to the cortex, attenuates the transmission of redundant and irrelevant sensory stimuli and thereby protects higher cognitive function from interference. Patients with SZ and their first-degree relatives exhibit sensory gating deficits that correlate with cognitive function and symptom severity. The goal of the present study is to determine whether sleep spindles and sensory gating are associated with the same underlying TRN mediated thalamocortical communication abnormality in schizophrenia and predict memory consolidation deficits and symptom severity. Measurement of sensory gating is more tractable and will enable large-scale genetic studies to decipher the complex genetic architecture of TRN dysfunction in schizophrenia, provide clues to mechanism and actionable targets for treatment.